New Multi-Doped Apatites as 3-D Porous Devices With Multifunctional Ability for Regenerative Medicine

The research activity described in the present thesis is devoted to the design and development of porous bioactive ceramic scaffolds addressed to the regeneration of bone tissue and was mainly carried out at the Institute of Science and Technology for Ceramics, belonging to the National Research Council of Italy (ISTEC-CNR), during my Ph.D. in Civil, Environmental and Mechanical Engineering (Curriculum B: Mechanics, Materials, Chemistry and Energy). The regeneration of critical size bone defects is still an unmet clinical need and since decades the development of bioactive scaffolds, capable to instruct and guide bone cells to tissue regeneration is a major research area in material science, including interdisciplinary approaches spanning from the field of chemistry, engineering, biology and medicine. In fact, the currently used bio-inert devices (e.g. metallic devices) can merely provide a mechanical support without regenerating the damaged bone tissue and often inducing adverse side effects such as infections while forcing the patient to frequent revision surgeries, with relevant socio-economic impact. The main aim of my work was the design and optimization of new materials and processes to produce bioactive ceramics implants as potential solution for the treatment of large and load-bearing bone defects, particularly suitable for cranio-maxillofacial, orthopaedic and spinal surgery. In my activity I synthesized new hydroxyapatite-based materials, Ca10(PO4)6(OH)2, exhibiting ionic substitutions designed to mimic the inorganic part of bone, particularly magnesium, strontium, zinc and carbonate, which increase the osteogenic ability and the bio-resorbability, promote the physiological bone turnover, thus suitable also for osteoporotic patients, as well as the antibacterial ability. After a general introduction of bone tissue physiology and an overview on the analytical methods involved in the research (Chapter I and Chapter II, respectively), my thesis focuses on the development of various hydroxyapatite nanophases showing multiple ionic substitutions including strontium or zinc ions, in association with magnesium and carbonate, with the purpose to provide synergistic biological effects such as osteogenic and antibacterial ability, and induce microstructural changes potentially improving the mechanical performance (Chapter III). In this Chapter, an important role was played by sintering, that was investigated varying different parameters like temperature and atmosphere (Air, CO2). The influence of doping ions and conditions of sintering was evaluated by chemical-physical, biological and mechanical characterization in order to understand how the presence of doping ions and different conditions of sintering influence the osteogenic properties and the mechanical behavior of the hydroxyapatite scaffolds. Then, Chapter IV describes novel nanocrystalline, multi-doped hydroxyapatite phases with excellent osteoinductive character and anti-infective properties, evaluated in collaboration with University of Pavia. Physico-chemical analysis highlighted the role of the surface state and charge, as induced by the ion doping, in the enhancement of the biological features. Finally, Chapter V describes the preparation of 3-D devices endowed where the porosity could be controlled and tailored to achieve suitable compromise between mechanical properties and porosity extent, relevant for bone invasion and osteointegration. The devices are obtained via direct foaming of multi-doped hydroxyapatite ceramic suspension with high-energy planetary ball milling. This method enabled the development of large and complex shape porous scaffolds, recapitulating composition, porosity and structure of the natural bone, thus promising for future practical applications in bone surgery. A better understanding of how dopant ions affect the mechanical properties of these scaffolds has been made possible thanks to the several mechanical and microstructural tests performed on them.